Ovarian Dendritic Cell Vaccine Trial

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The purpose of this study is to determine if an immune modifying drug (Ontak) alone or as part of a vaccine therapy will produce remissions in patients with advanced ovarian cancer. This research is being done because we want to find new therapies for treatment of relapsed or refractory (resistant to ordinary treatment) ovarian cancer. The use of ONTAK and vaccine therapy is research.

A new experimental approach for treating refractory or relapsed ovarian cancer involves using the patients own immune system to kill the cancer cells. These immune cells are called monocytes and are harvested from blood. The process of Leukapheresis collects the monocytes called Dendritic Cells. This is usually a 3 hour process done in the comfort of a hospital bed in the apheresis lab, similar to giving blood for donation. Approximately 300cc's are collected during this process, the equivalent of about 10 ounces of blood. Once these dendritic cells are collected - a special laboratory grows and processes them into a vaccine using a patient's own tumor cells. This preparation is then given back to the patient hopefully to stimulate the immune system to kill cancer cells. This type of treatment is considered biological research.

This study also involves a drug called ONTAK, which is made using certain proteins from diphtheria toxins and interleukin-2 (chemotherapy drug). This drug will act on immune suppressing cells normally present in your body making vaccine therapy possibly less effective. Ontak helps set up your immune system to be boosted by the vaccine injections. The use of Ontak followed by the vaccine to stimulate your tumor killing immune cells has not been done in ovarian cancer before and is research.

Condition or disease

Intervention/treatment

Phase

Ovarian Cancer

Biological: Ontak DCBiological: DC vaccinationDrug: Ontak

Phase 2

Detailed Description:

Patients with advanced ovarian carcinoma who have failed initial curative chemotherapy attempts will be evaluated at the time of relapse for tumor debulking surgery prior to the initiation of salvage chemotherapy. If appropriate, samples will be collected for tumor lysate preparation for vaccination as per the existing Loyola protocol. Lysates may also be produced by the collection of malignant effusions as performed for palliation of symptoms. Patients will then receive palliative chemotherapy to a maximum tumor cytoreduction. Patients from whom sufficient tumor cells have been collected for DC-based vaccine production will undergo a leukapheresis for DC cell production. Once completed, these patients will be randomly assigned one of two treatment groups: Cohort (Group) 1 - Administration of a single dose of Ontak at 18 μg/kg followed by DC vaccination with 1 x 106 tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals; or Cohort (Group) 2 - Identical DC vaccination as in Group 1 without Ontak pre-treatment. Patients for whom collection of tumor cells for lysate preparation is not possible will be assigned to Cohort (Group) 3, with administration of Ontak at the same dose without vaccination. In this pilot study we plan to treat 12 patients in each group over a two-year period of time. Therapy will begin four weeks after chemotherapy completion, given to achieve maximum cytoreduction prior to protocol therapy initiation

Administration of a single dose of Ontak at 18 µg/kg followed in 96 hours by DC vaccination with 1 x 10(6th) tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals (6 weeks)

Biological: Ontak DC

Administration of a single dose of Ontak at 18 µg/kg followed in 96 hours by DC vaccination with 1 x 10(6th) tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals (6 weeks)

Other Name: denileukin diftitox (Ontak)

Experimental: 2

DC vaccination with 1 x 10(6th) tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals(6 weeks)

Biological: DC vaccination

DC vaccination with 1 x 10(6th) tumor lysate and KLH-loaded immature DCs into inguinal nodes identified by ultrasound guidance for a total of three injections at two week intervals; (6 weeks)

Experimental: 3

administration of Ontak ,18 µg/kg at the same dose without vaccination.

To determine if immunoregulatory T-cell inhibition by Ontak followed by the administration of an autologous tumor lysate-loaded dendritic cell vaccine enhances the immune response in patients with relapsed/refractory ovarian cancer [ Time Frame: days 45 and 62 post vaccine ]

Secondary Outcome Measures :

To define the in vitro and in vivo responses of Ontak with and without DC vaccination. [ Time Frame: Days 46 and 62 post vaccine ]

To characterize the toxicities of this novel Treg/DC-based vaccination strategy. [ Time Frame: weekly assessments for a total of 4 weeks ]

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Ages Eligible for Study:

18 Years and older (Adult, Older Adult)

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Patients must have a histologic or cytologic diagnosis of epithelial ovarian cancer

Patients are eligible if they have failed to enter a complete remission with induction therapy or have relapsed after a period of remission and are not eligible for otherwise curative therapy

Patients must not have received any antineoplastic chemotherapy or immunotherapy for the four weeks preceding tumor excision; six weeks for nitrosoureas and mitomycin-C

Patients must not have received irradiation for the four weeks prior to removal of the tumor and no previously irradiated tumor deposits may be used for tumor lysate in the development of the dendritic cell vaccine

Age >18 years. Because no dosing or adverse event data are currently available on the use of Ontak in combination with dendritic cell vaccination in patients <18 years of age, children are excluded from this study but may be eligible for future pediatric phase 2 combination trials

Life expectancy of greater than three months

Karnofsky performance status must be >70%; (see appendix A)

Patients must have adequate baseline hematopoetic function as defined below. - The following labs must be drawn within four weeks of having the tumor harvested and/or receiving the dose of Ontak

total white blood cell count > 2,500/mm3

absolute neutrophil count > 1,000/mm3

absolute lymphocyte count > 500/mm3

platelet count > 80,000/mm3

Patients must have adequate baseline organ function as defined below. The following labs must be drawn within four weeks of having the tumor harvested and/or receiving the dose of Ontak:

total bilirubin ≤ 2.0 mg/dl

AST(SGOT)/ALT(SGPT) <2.5 X institutional upper limit of normal

creatinine ≤2.0 mg/dl

prothrombin time (INR) ≤1.5 X institutional upper limit of normal

albumin >3.0 mg/dl

If patients have had recent surgery, then they must be fully recovered from the effects of that surgery.

The effects of Ontak on the developing human fetus at the recommended therapeutic dose are unknown. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately.

Patients must have the ability to understand and the willingness to sign a written informed consent document.

Additional eligibility requirements for vaccine therapy initiation:

Patients are eligible after tumor collection for the vaccine strategy, or for those selected to receive ONTAK alone (group 3) because tumor is not available can enroll at ay time they fulfill the Eligibility Criteria. Pre-vaccination the goal is to establish a Minimal Residual Disease state (MRD maximum tumor diameter of any residual disease ≤ 1cm). This can be achieved with surgery and/or salvage chemotherapy. Ontak administration and/or vaccine therapy will commence at least 4 weeks after the completion of the last day of any of the aforementioned therapies

Patients to be randomized to groups 1 and 2 must have tumor available for preparation of tumor lysate vaccine

Women and members of all races and ethnic groups are eligible for this trial

Exclusion Criteria:

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

Patients may not be receiving any other investigational agents.

Patients who have received prior anti-tumor vaccines are ineligible

History of allergic reactions attributed to compounds of similar chemical or biologic composition to monocolonal antibodies from Murine sources

Pregnant and lactating women are excluded from this study. Because there is an unknown but potential risk for adverse events in nursing infants, breastfeeding should be discontinued if the mother is treated with Ontak. These potential risks may also apply to other agents used in this study

Patients with HIV infection, AIDS, or hepatitis B surface antigen positivity, are excluded from this trial. Patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy

History of corticosteroid use in the four weeks preceding entry onto the clinical trial, or the requirement for ongoing corticosteroid use during the study period

Patients who are expected to require therapeutic anticoagulation during the trial period